Small cell lung cancer (SCLC) is characterized by an aggressive clinical course and a dismal survival rate. Therefore there is an urgent need for novel therapeutic modalities for this lethal malignancy. Our results from the studies funded by the parent R15 grant showed that capsaicin (the spicy ingredient of chili peppers) displays potent apoptotic activity in SCLC in cell culture, in chicken chorioallantoic membrane (CAM) models and in athymic mice models. However, the clinical application of capsaicin is limited by its unpleasant side effects including gut pain, hyperalgesia, stomach cramps and nausea. This drawback could be circumvented by the design of capsaicin analogs, which retain the anti-tumor activity of capsaicin but do not produce the heat-sensation of the phytochemical capsaicin. Capsaicin has been used as a pain-relieving agent. Several convergent studies have identified capsaicin analogs which display potent pain-relieving activity without the `heat sensation'. However, the anti-tumor activity of these non-pungent capsaicin analogs is unknown. The aim of the present study is to compare the anti-tumor activity of three non-pungent analogs: capsiate, olvanil and arvanil. We also intend to examine if one of these non-pungent capsaicin analogs will sensitize platinum- resistant SCLCs to camptothecin-induced apoptosis. Our cell culture results showed that capsiate, olvanil and arvanil increased apoptosis, comparable to that of capsaicin. We also observed that capsaicin sensitized cisplatin-resistant SCLC cells to camptothecin-induced apoptosis. With this background, the central hypothesis of this grant is that the non-pungent capsaicin-analogs: capsiate, orvanil, and arvanil, will display potent apoptotic activity by themselves and in combination with camptothecin in vivo. One of the innovative aspects of our grant is that we aim to test the anti-tumor activity of these compounds against patient-derived, xenografted tumors in mice. In addition, we intend to measure the biodistribution of these compounds in tumor tissue, skin, lung and liver in mice. The studies in this R15 proposal will lead to the identification of novel capsaicin-based combination therapies against human SCLCs and provide meaningful research experiences for undergraduate and graduate students.